Stroke poses a significant healthcare burden in this country as it is the fourth leading cause of death and results in a significant amount of chronic disability (Towfighi and Saver 2011). Despite decades of research, there is presently no approved drug-based therapy that stimulates recovery of neurological functions in stroke patients (Endres, Engelhardt et al. 2008).
Several pharmacological drugs, such as carbamylate erythropoietin (Villa, van Beek et al. 2007), granulocyte-colony stimulating factor (Schabitz and Schneider 2006) and amphetamine (Barbay and Nudo 2009) enhance functional recovery and are currently being evaluated in clinical trials for stroke recovery. However, results from pharmacological studies suggest that multiple mechanisms contribute to different aspects of functional recovery and therefore several mechanisms must be targeted in developing stroke drug therapies to provide optimal functional restoration. Recently one research group found a selective sigma receptor agonist, SA4503, enhanced brain plasticity and improved sensorimotor function without decreasing infarct size (Ruscher, Shamloo et al. 2011). The researchers concluded that SA4503 may exert neuroprotective effects by enhancing cellular trafficking of biomolecules essential for brain repair.
Sigma receptors (σRs) are predominantly expressed at the endoplasmic reticulum (ER) and represent a structurally unique class of intracellular proteins that function as chaperones (Katz, Su et al. 2011). Ajmo and collaborators (Ajmo, Vernon et al. 2006) showed that the σ-1/σ-2 ligand N,N′-di-o-tolyl guanidine (DTG) decreases infarct size in a rat model of ischemic stroke. The authors suggested that this neuroprotective effect of DTG was probably due in part to the preservation of intracellular calcium homeostasis. The authors also showed that DTG dampened pro-inflammatory signals at delayed time points by decreasing the number of activated microglia and astrocytes, thereby preventing expansion of the ischemic core. When administered beginning 24 hours after permanent middle cerebral artery occlusion (MCAO), 1,3-di-o-tolylguanidine (DTG) decreased infarct size 96 hrs post-MCAO, but failed to improve long-term functional recovery (Leonardo, Hall et al. 2010).
Most rodent stroke studies have focused on mechanisms of neuronal injury and neuroprotection, and have largely neglected white matter injury following stroke. The inventors believe that drugs targeted only to gray matter will not be efficient in minimizing damage or sustaining functional recovery following stroke. White matter comprises 50% of human brain, is more sensitive to oxidative stress than neurons and is as equally affected as neurons in most cases of stroke (Ho, Reutens et al. 2005). It does not matter how many neurons are spared by a treatment, if there remains extensive damage to oligodendrocytes and white matter tracts, functional recovery will not be possible.
Sigma receptor (σ1R) agonist 1,3 di-o-tolylguanidine [DTG] decreased infarct volume in rats 96 hours after stroke, but the effect was not maintained long-term, and therefore, did not improve behavioral outcomes (Leonardo, Hall et al. 2010). Of the thousands of promising treatments tested in animals, the clot busters, tissue plasminogen activator (tPA) which restore blood flow remain as the only FDA approved drug. However, most patients do not receive tPA as they seek treatment beyond the narrow therapeutic window. Moreover, these drugs do not treat any of the pathophysiologic processes occurring after stroke. So it is an unmet need to target pathological process occurring at delayed time points after stroke.
What is needed is a composition and method of treating neurological disorders such as stroke which improves optimal long-term functional recovery.